Role and mitigation of inflammasomes and inflammation during covid-19

Active Project Grant Awarded Last action

Award ID
R01AI158314
Recipient
Awarding agency
Obligated
$6,406,840

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 87% complete
Funding
  • $5,835,413.30 Federal
  • $571,427.00 Non-federal
Place of performance
Chapel Hill, NC 27599, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The covid-19 pandemic caused by sars-COV-2 has resulted in swift and catastrophic losses of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most detrimental outcomes of covid-19 infection that can lead to the rapid deterioration and death of patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of inflammatory cytokines during the late stages of covid-19. The master cytokines that are thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor (TNF). Currently two clinical trials have shown the efficacy of IL-1 inhibitor in covid- 19 patients. However, in many cases, the mechanism and impact of these cytokines during sars-COV-2 infection are poorly understood. An in-depth mechanistic understanding of cytokine induction is important because this understanding will significantly impact the design and success of ARDS treatment. This application focuses on the role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine, IL-1SS, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase 1 activation, which then cleaves pro-IL-1SS and pro-IL-18 to mature IL-1SS and IL-18. In addition to the release of IL-1SS and IL- 18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is comprised of a receptor or sensor, with the most prominent ones represented by NLRP1, NLRP3, NLRP6, NLRC4 and AIM2. IT also includes an adaptor molecule ASC (apoptosis-associated speck-like protein containing a card), and the effector caspase-1. Each receptor or sensor can be activated by specific pathogen products called pamps or cell damage associated molecules called damps. Single cell rnaseq data from covid-19 patients show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of severe covid-19 patients. In addition, we find a bidirectional feed- forward loop of inflammasome activation and inflammatory cytokine induction involving myeloid cells and airway stromal cells. This proposal will test the hypothesis that this two way amplification loop is important in covid- 19.

Transactions

Action Federal Non-federal Date
Amendment $616,371 $0
Amendment $617,741 $0
Amendment $619,067 $0
Amendment $620,359 $0
Amendment $620,359 $0
Amendment $151,936 $0
Amendment $151,936 $0
Amendment $151,936 $0
Amendment $571,427 $0
Amendment $571,427 $571,427
Amendment $571,427 $0
Original award $571,427 $0
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Subawards

Subrecipient Amount Awarded
Duke University The Duke University research team will provide access to BSL3 and ABSL3 laboratory environment, safety training/oversight and perform selected small animal… $360,000

Quick answers

Who received award R01AI158314?

R01AI158314 was awarded to University Of North Carolina At Chapel Hill by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 15, 2022.

How much is award R01AI158314 worth?

$6,406,840 has been obligated on R01AI158314: $5,835,413 in federal funding and $571,427 in non-federal funding.

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